An Efficient and Enantioselective Approach to 2,5-Disubstituted ­Dihydropyrones

Abstract

A highly efficient method for the formation of optically active 2,5-disubstituted dihydropyrones using catalytic enantioselective hetero-Diels-Alder reaction of (E)-3-methyl-4-methoxy-2-[(trimethylsilyl)oxy]-1,3-butadiene with aldehydes is presented. In the presence of 5 mol% chiral titanium(IV) complex, this catalytic reaction proceeded smoothly to afford corresponding dihydropyrones in moderate to excellent yields with high enantioselectivities (up to 99% ee).

Key words

hetero-Diels-Alder reaction - titanium complex - asymmetric catalysis - dihydropyrones

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9

The following are the NMR data of diene 3: ¹H NMR (300 MHz, CDCl₃): δ = 6.52 (s, 1 H), 4.24 (s, 1 H), 4.13 (s, 1 H), 3.68 (s, 3 H), 1.70 (s, 3 H), 0.25 (s, 9 H).

10

A Typical Experimental Procedure is Given for the Synthesis of 2,3-Dihydro-5-methyl-2-phenylpyran-4-one: A mixture of (R)-BINOL (7.2 mg, 0.025 mmol), Ti(Oi-Pr)₄ (1 M in toluene, 12.5 µL, 0.0125 mmol) and finely powdered 4 Å MS (120 mg) in THF (0.5 mL) was heated at 35 °C for 1 h. After the brown mixture was cooled to -18 °C, benzaldehyde (26 µL, 0.25 mmol), diene (84 µL) and THF (0.5 mL) were added successively. The reaction was allowed to stir at 0 °C for 48 h, after this time it was removed from the bath, and treated with TFA (100 µL). After stirring 12 h at r.t., the reaction was quenched with sat. NaHCO₃ (5 mL), filtered through a plug of Celite, extracted with Et₂O (10 × 5 mL). The organic layer was dried over Na₂SO₄ and concentrated. The crude residue was purified by flash chromatography (9:1 PE^a: Et₂O) to yield 2,3-dihydro-5-methyl-2-phenylpyran-4-one (40.6 mg, 86% yield) as white crystals. The isolated material was determined to be in 99% ee by HPLC analysis (Daicel Chiralcel OJ, 254 nm UV detector, 90:10 hexane:2-propanol, t _R(minor) = 15.40 min, t _R(major) = 21.15 min). ¹H NMR (600 MHz, CDCl₃): δ = 7.40-7.46 (m, 5 H), 7.39 (s, 1 H), 5.39-5.42 (m, 1 H), 2.88-2.94 (m, 1 H), 2.69-2.73 (m, 1 H), 1.76 (s, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 192.59, 159.49, 138.27, 128.80, 128.78, 126.05, 114.14, 80.99, 43.21, 10.51. The chromatograms are illustrated in Figure [1] .